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From Tufts to a Cure for Cancer

Ph.D. student Tim Siegert and his chemistry colleagues use creativity (and computers) to stop cancer in its tracks

From his bench in the Kritzer Lab on Tufts University’s Medford campus, 4th year Ph.D. candidate Tim Siegert is synthesizing brand-new molecules from scratch that could point the way to powerful new treatments for cancer.

Siegert notes that only a handful of other chemistry labs are doing what they do at Tufts, which is equal parts information science, molecular engineering and old-fashioned lab experimentation.

“Using computers, we can design a molecule on Monday, make it in the lab, and test its biological effects on Friday,” Siegert says.

Tufts Professor Joshua Kritzer, an award-winning teacher and researcher who earned his Ph.D. in biophysical chemistry from Yale, runs the lab staffed by six graduate students like Siegert, two post-doctoral fellows, and four Tufts undergraduates.

Under Kritzer’s enthusiastic mentorship, Siegert and the rest of the student research team are hot on the trail of so-called “undruggable” proteins, building blocks of cells that play a critical role in the transmission of faulty chemical signals that trigger diseases like cancer.

When cells communicate with each other, Siegert explains, they do it through chemical signals that are often transmitted between two proteins. Not all of those signals are good for us. In cancer, for example, the genetic switch that controls cell division gets locked in the “on” position, causing explosive growth. If we can block the transmission of that “on” signal, we could stop cancer in its tracks.

Unfortunately, it’s not always that simple. Some proteins have a “binding crevice,” a groove in their surface into which other proteins can easily attach, like a key in a lock.

“Those are called “druggable” proteins, because they already have a molecule binding site,” says Kritzer. “The problem is that these druggable proteins only represent 20 percent of the human genome.”

For the other 80 percent, scientists are dealing with proteins like the ones that bind with DNA, which have large, flat surfaces instead of a handy crevice.

“It’s much harder to design a molecule to wedge in there,” says Kritzer.

But that’s exactly what Kritzer and Ph.D. student Siegert are trying to do, design three-dimensional synthetic molecules — using handmade strings of amino acids called “cyclic peptides” — that are precisely the right shape and size to attach to these flat, awkward protein surfaces.

“If we can block the protein-to-protein interaction with something that we make synthetically,” explains Siegert, “then we can use that as a chemical probe or a potential drug to prevent that original interaction” — the misfiring signal that causes cancer, for example — “from occurring.”

The first step is to find the right protein to test their hypothesis. Siegert and his lab mates consulted an online protein databank compiled by researchers worldwide. Instead of rummaging through 40,000 specimens looking for the best candidate, they did what any good 21st century scientist does: they wrote a computer program.

“Science today has to be done very differently than it was even 20 years ago,” says Kritzer. “A Ph.D. in chemistry doesn’t mean you’re doing only chemistry. There aren’t these little cloistered disciplines of computer science, engineering, biology, chemistry, medicine, etc. Modern science requires a lot of cross-talk.”

Instead of assigning Siegert a specific protein or a disease process to pursue, Kritzer encourages his graduate students to choose a problem or process that personally fascinates them.

“One of the greatest things about our lab is that we’re not pigeonholed into certain diseases or certain pathways,” says Siegert. “As grad students, we’re encouraged to try to find a project that we find really interesting and go after that using the toolbox that we’re developing.”

Kritzer believes the type of groundbreaking original research conducted by graduate students like Siegert is science at its most creative, applicable and interdisciplinary, exactly the type of work that distinguishes all of Tufts’ graduate programs.

“At Tufts, we want to prepare people for their dream job and their dream career,” says Kritzer. “We’re not some ‘ivory tower’ teaching young people to be clones of ourselves. We’re giving people skills they need for real jobs, and we’re preparing them as rigorous scientists, so they can succeed in whatever career they choose.”

For Siegert, that dream job may be right outside the campus gates.

“A couple of pharmaceutical and biotech companies that are using cyclic peptides as potential drugs are located in Cambridge,” says Siegert. “In terms of getting to know people from industry, being located in Medford — right near Boston — is super advantageous. There are nearby lectures and networking events every month for people in our field.”